5-Acetyl-4,6-dimethyl-2-[2-[4-(2-methoxyphenyl)piperazinyl]ethylamino]pyrimidine trihydrochloride represented by the following structural formula:
(hereinafter referred to as the compound of the present invention) has an α-blocker activity and is useful as a therapeutic agent for urinary disturbance (JP-A-62-51672, JP-A-3-90027 (U.S. Pat. No. 5,075,308)).
Although the compound of the present invention is stable, it has a property of being quick in both absorption and metabolism, so that its effective blood concentration cannot be maintained for a prolonged period of time. That is, as shown in FIG. 1 regarding the blood concentration pattern when a conventional tablet (the tablet produced in Comparative Example 1 which is described later containing 3 mg of the compound of the present invention) is orally administered, the effective blood concentration can be maintained for merely about 5 hours. Accordingly, it is necessary to administer the compound of the present invention repeatedly at relatively small doses in order to keep its activity and effect as an α-blocker.
In order to solve the problem, the present inventors have made an attempt to make the compound of the present invention into a sustained-release formulation.
When a sustained-release formulation is prepared, it is generally carried out to coat the periphery of a granule or a tablet with a sustained release film. The inventors also have examined on this technique in various manners and verified as a result that a drug can be released continuously for 12 hours or more by sustained-release formulations using ethyl cellulose and an ethyl acrylate-methyl methacrylate-ethyl trimethylammoniumchloride methacrylate copolymer (Eudragit RS30D, trade name, Rohm Pharma) as the release controlling membranes. However, each formulation could not show a constant releasing pattern due to great influence of pH on the dissolution rate and was lacking in stability due to periodical coloring.
Based on an assumption that the compound of the present invention of being hydrochloride would be the cause of the unstable releasing pattern and periodical unstableness of the above formulations, the inventors have conducted intensive studies on sustained-release formulations using those films which are not influenced by acid, namely water-insoluble films having no hydrophilic group, as the sustained release films. As a result, formulations capable of keeping their activities and effects and showing a constant releasing pattern and also having periodical stability were obtained, thereby resulting in the accomplishment of the present invention.